Publication: CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan

Thomas R. Cox, Aug 2019

CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan

We are super excited to announce that our recent work in close collaboration with A/Prof Paul Timpson has just been published in Nature Communications (view the full Open-Access article here)

In this work (which was a large international collaboration), co-led by our team and Paul Timpson’s team (also at the Garvan Institute), we show that remodeling of the stromal  tissue in and around pancreatic tumours may be the key to stopping their spread and improving chemotherapy outcomes.

Cancer cell CAF crosstalk

What we did

We already know that tumours are made up of heterogenous populations of cancer cells with different mutational landscapes. Furthermore, recently, the field has begun to realise that the cancer associated fibroblasts (CAFs) present in and around the tumour are also a diverse collection of  subpopulations.

What we show in this paper, is that different mutational burdens in tumour cells (p53 mutation vs. p53 loss) leads to changes in the tumour cell secretome. These different tumour cell secretomes then differentially educate cancer associated fibroblasts in the tumour, to trigger them to remodel the local extracellular matrix (ECM). Part of this remodelling is the secretion of heparan sulfate proteoglycan 2 (HSPG2), also known as Perlecan. The high levels of Perlecan secreted by p53-mutant cancer cell educated CAFs (mut-e-CAFs), leads to the generation of a pro-metastatic and chemo-protective tumour microenvironment. As a result, these mut-e-CAFs create a tumour microenvironment that facilitates cancer cell spread around the body and also protects the cancer cells from standard-of-care front-line chemotherapy (gemcitabine + Abraxane).

We show that blocking the deposition of Perlecan by CAFs reduces the pro-metastatic influence of the tumour microenvironment and re-sensitises the pancreatic cancer cells to standard-of-care front-line chemotherapy, improving survival. These data support the emerging idea that co-targetting the pancreatic cancer microenvironment offers a viable therapeutic approach to improving outcome and survival in patients.

Pancreatic tumour - Matrix and Metastasis

Abstract

Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs. We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.

Links

View article on the Nature Communications website
Download the PDF here
Read the Garvan Institute Press Release

Citation

Vennin et al. CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoprotective environment via perlecan
Nature Communications (2019) | doi:

Key Words

Pancreatic Cancer, Perlecan, Extracellular Matrix, Chemotherapy

Funding

This work was supported by NHMRC, Cancer Council NSW, Cancer Institute NSW (M.N., D.H., and T.R.C), Len Ainsworth Pancreatic Cancer Fellowship (P.T.) and Philip Hemstritch Pancreatic Cancer Fellowship (M.P.), Royal Australasian College of Physicians Research Foundation scholarships, a CRUK core grant, an NBCF fellowship (D.R.). This project was made possible by an Avner Pancreatic Cancer Foundation Grant. P.T. is a recipient of an NHMRC Senior Research Fellowship, C.V. is a recipient of a post-doctoral HFSP fellowship, T.R.C. is a recipient of an NHMRC RD Wright Biomedical Career Development Fellowship, A.W.B. was supported by the Royal Society of NZ James Cook Fellowship and Health Research Council of NZ research grants. Y.W. was supported by a United States NIH CA204704 and CA209629. B.L.P. is a recipient of an NHMRC Early Career Fellowship.