Research

Basic Science and Translational Research is being conducted both individually and collaboratively by the members of the NYPOG to better understand how the tumor microenvironment affects disease progression and how therapies currently used to treat cancer affect the tumor microenvironment. NYPOG assists in these efforts by providing expertise in the areas of research outlined below:

a. Dissemination

Cancer cells within the tumor microenvironment are known to be genotypically and phenotypically heterogenous. Only a minority of cells can migrate across the endothelial barrier of the vasculature within the primary tumor; one of the first steps in the metastatic cascade. NYPOG researchers determined that the actin regulatory protein MenaINV is required for transendothelial migration of breast cancer cells (Pignatelli et al, 2014) and identified intravasation portals, called TMEM doorways, for hematogenous breast cancer cell dissemination to distant sites (Harney et al, 2015, NIH Director’s blog). NYPOG researchers also determined the phenotype of cancer cells that facilitates MenaINV-mediated invasion and dissemination called MenaCalc. Both TMEM doorways (Rohan et al, 2014, and Sparano et al, 2017) and MenaCalc (Agarwal et al, 2012, and Forse et al, 2015) are clinically validated biomarkers of metastasis. Furthermore, NYPOG researchers determined that TMEM doorways are also present at metastatic sites (Ginter, et al, 2019) and began to elucidate the micro-pharmacology of TMEM doorway function (Duran, et al, 2025).

b. Stemness

Successful colonization of distant sites, i.e. onset of proliferation of cancer cells and development of metastatic foci, requires the activation of a stem phenotype in tumor cells. A high proportion of cancer stem cells (CSCs) in primary tumors is associated with poor prognosis and increased metastatic relapse. CSCs have an enhanced ability to self-renew which makes them uniquely capable of initiating and sustaining primary and metastatic tumor growth. Importantly CSCs are intrinsically more therapy-resistant than their more differentiated progeny. NYPOG researchers determined that macrophages (immune cells within the tumor microenvironment) can induce non-stem cancer cells to become stem. NYPOG researchers described the behavior of CSCs in vivo and used human tissue samples obtained from patients to determine the positive correlation between CSC density and TMEM doorway score (Sharma, et al, 2021). This is important because it may be used to develop prognostic biomarkers regarding disease outcome or to predict response to chemotherapy.

c. Dormancy

An important concept in cancer biology and cancer outcome is the ability of disseminated cells to remain dormant for many years before they initiate proliferation. Indeed, some types of breast cancer are notorious for late relapse, which can occur even 25 years after the initial diagnosis. It is important to better understand factors that regulate dormancy and determine if this knowledge can be used for prognostication and evaluation of treatment options. We are making progress in understanding the role of tumor microenvironment in regulating dormancy and its effect on metastasis (Linde et al, 2016; Harper et al, 2106). Furthermore, NYPOG research determined how the microenvironments of primary (Borriello, et al, 2022) and target organ niches may affect disseminated dormant cells (Dalla, et al, 2024) and began to discover therapeutics for preventing awakening of dormant cancer cells.

d. Differences in Outcomes

It is well known that some cancers behave more aggressively in patients of certain racial and ethnic backgrounds. For example, Black patients with breast and prostate cancer have lower overall survival compared to other races. The reasons for these disparities are still not fully understood, but it is now clear that biological factors play a major role cancer progression and response to therapy. These biological factors could also affect the response to chemotherapy. Indeed, we have preliminary evidence that Black patients have worse distant recurrence-free survival when treated with pre-operative (neoadjuvant) chemotherapy than non-Black patients (Pastoriza et al, 2018). NYPOG studies aim to determine to what extent the tumor microenvironment is responsible for these differences in cancer outcome (Kim et al, 2020).

e. Biomarker Development

The ability to determine disease outcome and predict response to treatment depends on the availability of robust biomarkers. There are many biomarkers associated with cancer proliferation. However, markers that can predict cancer cell dissemination are lacking. Since ~90% of cancer related mortality is due to metastatic disease, and metastatic disease depends on the ability of cancer cells to travel to distant organs, developing markers that can distinguish metastatic from non-metastatic cancers, and responsive cancers from those resistant to chemotherapy, is critical. NYPOG researchers are currently focused on evaluating their published markers of dissemination (Sparano et al, 2017, Entenberg et al, 2020) in multi-ethnic cohorts. Interestingly, certain subsets of patients have been found to have an increased TMEM-doorway density and MenaINV expression in residual tumor after chemotherapy, a previously unrecognized form of chemotherapy resistance (Karagiannis et al, 2017) that needs to be evaluated further to determine if some races are more prone than others to this type of resistance. We aim to combine basic science insights and advanced digital pathology technologies to distinguish which patients are likely to develop metastases and respond well to chemotherapy. To this extent NYPOG research determined that TMEM doorway score may serve as a prognostic marker of metastasis even in the residual cancer after chemotherapy (Kim et al, 2020) and have preliminary evidence that TMEM doorway score may serve as predictive biomarkers for chemotherapy selection.