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Displaying One Session

Channel 1 Proffered Paper session
Date
21.09.2020
Time
16:20 - 18:00
Room
Channel 1
Chairs
  • Daniel Peeper (Amsterdam, Netherlands)
  • Colinda Scheele (Leuven, Belgium)
Proffered Paper - Basic Science Proffered Paper session

1O - A study of cancer dissemination from metastatic intermediates of hypermethylated colorectal patients reveals a new mode of collective migration

Presentation Number
1O
Lecture Time
16:20 - 16:32
Speakers
  • Emmanuel Dornier (Villejuif, France)
Room
Channel 1
Date
21.09.2020
Time
16:20 - 18:00

Abstract

Background

Colorectal cancer (CRC) is the second most deadly cancer. Amongst the different types of CRCs, the hypermethylated subtype (CIMP) is the most aggressive. In a previous study, we identified that CIMP CRCs are able to form a new metastatic intermediate consisting of clusters of a hundred cells found in the peritoneal cavity of metastatic patients. Furthermore, these collective structures can also be found in the primary tumour. Importantly, when invading they only exist as collectives and do not show any sign of adhesion with the extracellular matrix or cell protrusion which are characteristics of collective mesenchymal migration, the only mode of collective dissemination described to date. These data suggest that CIMP clusters are using a new mode of invasion resembling the amoeboid movement of single cells, never described before.

Methods

We used microfluidics coated with non-adhesive polymer.

Results

We find that CIMP and colorectal cell line clusters confined in non-adhesive microchannels are able to move, independently of the formation of focal adhesions or protruding leader cells. Their migration speed ranged between 70 to 150μm/day, in line with observed cancer spread in vivo. We show that clusters display a supra-cellular actin cortex with increased contractility towards the rear of moving clusters, indicated by Myosin-II accumulation. This is a typical feature of amoeboid motion, where Rho activity is more intense towards the back. Indeed, interfering with ROCK or myosin activation strongly opposed migration. Moreover, using optogenetic tools we show that Rho activation at the back of the cluster is sufficient to promote migration.

Conclusions

By studying primary cancer specimens and cell lines from colorectal cancer, we demonstrate the existence of a second mode of collective migration, presenting the hallmarks of amoeboid migration, that we named collective amoeboid. This mode could be use by other cancer clusters when confronted to non-adhesive interfaces like the lumen of lymphatic vessels. This work suggests that therapies targeting adhesive properties of cancer cells might be unsuccessful and unravels a new therapeutic avenue to limit the metastatic spread of CRCs.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Proffered Paper - Basic Science Proffered Paper session

1977O - Functional inactivation of E-cadherin drives EMT-less metastasis

Presentation Number
1977O
Lecture Time
16:32 - 16:44
Speakers
  • Saverio Alberti (Messina, Italy)
Room
Channel 1
Date
21.09.2020
Time
16:20 - 18:00

Abstract

Background

Tumor metastasis is the main cause of death of cancer patients and the biggest hurdle for cancer cure. The identification of decisive drivers of metastasis is thus an urgent therapeutic need.

Methods

Cancer cell spheroids, wound healing and cell aggregation assays were utilized to explore cell-cell adhesion capacity. Immunofluorescence confocal microscopy and flow cytometry analysis were utilized to quantify expression of target proteins, IHC analysis quantified the expression of target molecules in primary tumors and metastases. Pre-clinical models of orthotopic growth of colon cancer and metastatic diffusion to the liver were utilized. Xenotransplant transcriptome analysis assessed EMT determinant transcription. Patients: 24 distinct case series of breast, colon, uterus, ovary, stomach, lung, and pancreatic cancers, for a total number of 13,042 primary tumors were analyzed. Kaplan–Meier plots were used to illustrate survival and metastatic relapse in investigated cohorts.

Results

We identify functional inactivation of highly expressed E-cadherin as a pivotal driver of metastatic diffusion in human cancer. E-cadherin is inactivated by binding to Trop-2, which causes release from the cytoskeleton, loss of cell-cell adhesion and activation of β-catenin, while maintaining epithelial differentiation. This leads to anti-apoptotic signaling, increased cell migration capacity and enhanced cancer cell survival. This global, Trop-2/E-cadherin/β-catenin-driven pro-metastatic program was recapitulated in human cancer, and was shown to profoundly impact on breast, colon, ovary, uterus, stomach cancer metastatic diffusion.

Conclusions

We identify functional inactivation of E-cadherin by Trop-2 as a pivotal driver of EMT-less metastatic diffusion in human cancer. This global, Trop-2/E-cadherin/b-catenin–driven pro-metastatic program profoundly impacts on the survival of patients bearing breast, colon, uterus, ovary, stomach, lung, pancreas tumours, paving the way for novel diagnostic procedures and anti-cancer therapies.

Legal entity responsible for the study

The authors.

Funding

Italian Ministry of Development (MI01_00424) and of University and Research (SCN_00558). M.T. was supported by the Programma Per Giovani Ricercatori “Rita Levi Montalcini” (Grant PGR12I7N1Z).

Disclosure

All authors have declared no conflicts of interest.

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Proffered Paper - Basic Science Proffered Paper session

Invited Discussant 1O and 1977O

Lecture Time
16:44 - 16:54
Speakers
  • Colinda Scheele (Leuven, Belgium)
Room
Channel 1
Date
21.09.2020
Time
16:20 - 18:00
Proffered Paper - Basic Science Proffered Paper session

Q&A and live discussion

Lecture Time
16:54 - 17:04
Speakers
  • Daniel Peeper (Amsterdam, Netherlands)
Room
Channel 1
Date
21.09.2020
Time
16:20 - 18:00
Proffered Paper - Basic Science Proffered Paper session

2O - Growth differentiation factor 15 (GDF-15) neutralization reverses cancer cachexia, restores physical performance and mitigates emesis associated with platinum-based chemotherapy

Presentation Number
2O
Lecture Time
17:04 - 17:16
Speakers
  • Zhidan Wu (Cambridge, United States of America)
Room
Channel 1
Date
21.09.2020
Time
16:20 - 18:00

Abstract

Background

Cancer cachexia is a metabolic disease characterized by unintentional weight loss, anorexia, muscle and fat wasting, fatigue and muscle weakness, chronic inflammation, all of which being contributing factors to poor quality of life and survival in patients. It’s well established chemotherapies, most often used to treat cancers are associated with adverse effects such as weight loss, emesis/nausea, leading to limited tolerability and effectiveness of treatment. GDF-15 is a cytokine reported to cause anorexia, aversion/emesis and weight loss in preclinical models and is associated with cancer cachexia and poor survival in patients. GDF-15 inhibition was effective to reverse weight loss, muscle and fat loss in mouse tumor models. Interestingly, it remains unclear whether increased skeletal muscle mass by GDF-15 inhibition results in restoration of muscle function. GDF-15 is also associated with platinum-based chemotherapy-induced adverse effects, however, a causal role for GDF-15 in mediating the emetic response has not been established.

Methods

We investigated these questions in a mouse tumor model, TOV21G and non-human primates (NHP) using a potent and selective monoclonal antibody (mAB1) that neutralizes circulating GDF-15.

Results

Treatment with mAb1 completely reversed tumor-induced cachexia including weight loss, lean and fat mass loss as well as declined muscle function and physical performance in tumor bearing mice. We show that cisplatin-induced weight loss and anorexia is GDF-15 dependent in mouse. In addition, Cisplatin induced GDF-15 circulating level and emesis in NHP and mAB1 treatment markedly attenuated cisplatin-induced emesis. Importantly, the preclinical findings are supported by patient data where we demonstrate an association between elevated circulating GDF-15 levels and platinum-based chemotherapy use.

Conclusions

Our findings indicate GDF-15 is a key regulator of cancer cachexia and chemotherapy-induced malaise. GDF-15 inhibition holds the potential as an effective therapeutic approach in combination with chemotherapy to alleviate GDF-15 mediated malaise, declined physical function and cachexia in patients.

Legal entity responsible for the study

Pfizer.

Funding

Pfizer.

Disclosure

Z. Wu: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. D. Bennett: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer; Shareholder/Stockholder/Stock options: Gilead Sciences. J. Brosnan: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. R.A. Calle: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. S. Collins: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. R. Esquejo: Full/Part-time employment: Pfizer. S. Joaquim: Full/Part-time employment: Pfizer. A. Joyce: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. H. Kim: Full/Part-time employment: Pfizer. B. LaCarubba: Full/Part-time employment: Pfizer. L. Lin: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. J.Y. Kim-Muller: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. M. Peloquin: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. B. Pettersen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. S. Qiao: Full/Part-time employment: Pfizer. M. Rossulek: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. G. Weber: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. B. Zhang: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer; Shareholder/Stockholder/Stock options: Lilly; Shareholder/Stockholder/Stock options: Merck; Officer/Board of Directors: Board of Director and SAB member for Keystone Symposium. M. Birnbaum: Leadership role, Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer. D. Breen: Shareholder/Stockholder/Stock options, Full/Part-time employment: Pfizer.

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Proffered Paper - Basic Science Proffered Paper session

3O - Efficacy of the triple combination of Estrogen Receptor, CDK4/6 and PI3K pathway inhibitors in ex-vivo models of breast cancer

Presentation Number
3O
Lecture Time
17:16 - 17:28
Speakers
  • Anna Diana (Napoli, Italy)
Room
Channel 1
Date
21.09.2020
Time
16:20 - 18:00

Abstract

Background

Activation of the Phosphatidylinositol 3-kinase (PI3K) pathway is common in Estrogen receptor (ER)-positive breast cancer (BC) and it has been associated with resistance to endocrine therapies (ET). The crosstalk between the Cyclin-dependent kinase 4/6 (CDK4/6) and PI3K pathways represents a strong rationale for co-targeting both axes to inhibit tumor growth. Moreover, combined treatment with PI3K and CDK4/6 inhibitors has been shown to overcome CDK4/6 inhibitor resistance in BC cells. We investigated the triple combination of ER, CDK4/6, and PI3K pathway inhibitors in ex vivo BC models as a novel strategy to overcome endocrine and CDK4/6-resistance.

Methods

We generated 25 ex vivo three dimensional spheroid culture models (organoids) from ER-positive BC samples, obtained from patients at surgery. After 5 days of treatment, we investigated anti-proliferative effects by MTT assay in these models with single agents, dual and triple combinations of Fulvestrant (F), Palbociclib (P) and Taselisib (T) as models of ET, CDK 4/6 and PI3K pathway inhibitors, respectively. We are also performing NGS analysis of both organoids and surgical samples to investigate predictive genomic biomarkers.

Results

Our results demonstrated that combination of F, P and T had a synergistic effect on the inhibition of spheroids proliferation in ≈30% of the examined samples compared to single drug treatments. Two subgroups of samples with different behavior were identified: one group showed no effect after single or triple treatment with only ≈15% reduction in cell viability (probably resistant) while the other group exhibited greater sensitivity to treatments (e.g. lobular histotype). Ongoing NGS analysis including a full panel of cancer-related genes, such as genes involved in CDK and PI3K pathways resistance. We will analyze concordance between surgical samples and ex vivo models in terms of genomic features and we will explore predictive role of genomic alterations.

Conclusions

The results showed an encouraging activity of the triple combination of ER, CDK4/6, and PI3K pathway inhibitors in ex vivo models of ER-positive BC. The different effect of the treatments could suggest a correlation between mutation setting and individual response.

Legal entity responsible for the study

University of Campania.

Funding

Pfizer.

Disclosure

All authors have declared no conflicts of interest.

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Proffered Paper - Basic Science Proffered Paper session

Invited Discussant 2O and 3O

Lecture Time
17:28 - 17:38
Speakers
  • Vincent Dezentje (Amsterdam, Netherlands)
Room
Channel 1
Date
21.09.2020
Time
16:20 - 18:00
Proffered Paper - Basic Science Proffered Paper session

Q&A and live discussion

Lecture Time
17:38 - 17:48
Speakers
  • Daniel Peeper (Amsterdam, Netherlands)
Room
Channel 1
Date
21.09.2020
Time
16:20 - 18:00