An integrated approach to melanoma metastasis and therapy resistance: effects of age-related changes in the ECM and the biomechanics of the skin

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Project Summary Chronic inflammatory conditions such as aging and obesity harmonize with cancer cell mutations to trigger and promote tumor development and progression. Hence, just like in melanoma, age plays an important role in pancreatic cancer (PC). A unique aspect of solid cancers (including melanoma, colon, lung, PC and others) is a non-cancer cell local reaction known as desmoplasia that, akin to chronic fibrosis, limits the normal organ function and promotes a pro-tumor systemic inflammation. Of note, PC’s desmoplasia can encompass over 70% of the tumor mass. Cancer-associated fibroblasts (CAFs) and their self-generated fibrous collagen rich extracellular matrix (ECM) are the main desmoplastic components and together regulate numerous aspects of cancer progression including drug resistance, immune cell regulation and metastasis. Importantly, while local fibroblasts and their ECM maintain homeostatic equilibrium of a healthy organ and can even prevent tumor development, chronically altered fibroblastic cells, like CAFs and their remodeled ECMs, sustain a dynamic reciprocity that upholds the cancerous (i.e., chronically diseased) organ. Yet, clinical attempts to eliminate pancreatic CAF/ECM render no benefit or were harmful to patients. Hence, “normalizing” the tumor microenvironment to harness its anti-tumor effects, as opposed to eliminating desmoplasia, is sought by the tumor microenvironment field. We and others have developed means to assess desmoplastic signatures using pathological samples. Of note, the only clinical intervention with a curative intent in PC is surgery, and pre-operatively treating surgical patients with chemo-radiation has been shown to often improve outcomes. A particular predicament of pre-operative chemo- radiation is that if surgery did not successfully eliminate all cancerous cells, the treatment could “aggravate” desmoplasia and promote fast progression of residual disease. One of the main known indicators of pro-tumoral desmoplasia is TGFβ, and we have demonstrated that desmoplastic signatures representative of avid TGFβ signaling are indeed predictive of short PC surgical patient overall survival. Published data using pre-clinical models indicated that TGFβ, is systemically increased by classic chemo-radiation. Nonetheless, data showed that if radiation is delivered in pulses, TGFβ levels are limited. This study proposes to conduct two specific aims: Aim1 will test if delivering radiation in pulses could “normalize” TGFβ secretion by human PC CAFs. For this we will use our well-established laboratory culturing model of desmoplasia using patient CAFs and their ECM. Aim2 will test whether detecting and measuring PD CAFs indicative of limited TGFβ signaling could be used as a desmoplastic indicator of improved patient outcomes. For this, we will use available pathological samples to compare melanoma vs. PC desmoplastic features and query their clinical relevancies. The proposal was designed to augment our knowledge on pro-tumoral CAF function and uncover potential means to deterred it.