McAllister Lab Research

 

Overview
Recurrence of cancer in the form of metastatic disease accounts for more than 90% of cancer deaths; however, tumor metastasis is considered an inefficient process whereby disseminated tumor cells remain undetected for protracted periods of time. Remarkably little is known about processes that serve to convert indolent tumors – such as the metastases that disseminate from a primary tumor – into overt, life-threatening tumors. Our research is focused on identifying systemic factors that contribute to tumor progression and finding ways to interdict their function. It is our hope that such information will ultimately lead to new therapies to treat cancer patients.

Discovery of Systemic Instigation
Our prior work lead to the discovery that certain indolent tumor cells can respond to systemic cues to become overt, detectable tumors. These systemic cues were actually generated by aggressively growing tumors located at distant anatomical sites. Thus, we found that human breast carcinomas (termed “Instigators”) facilitate growth of otherwise-indolent tumor cells and micrometastases (termed “Responders”) located in different anatomical sites. We termed this action-at-a-distance “Systemic Instigation”. Therefore, we think of cancer as a disease that is capable of actively perturbing as well as responding to the systemic environment. The view that tumor cells escape detection and remain indolent for protracted periods is not limited to disseminated tumor cells, but can also apply to primary tumors. 

instigation-diagram

The systemic instigation cascade. Primary instigating tumors secrete soluble osteopontin (OPN) into the circulation; OPN activates the host bone marrow and stromal precursor cells are mobilized into the circulation; bone marrow-derived cells are incorporated into the distant tumor stroma, thereby facilitating outgrowth of the once-indolent responding tumors.

Building a molecular framework of the systemic instigation cascade
We identified a molecular mediator that is necessary but not sufficient for systemic instigation – tumor-derived osteopontin (OPN). The relevance of OPN expression to human cancer pathogenesis has been revealed by studies showing that OPN expression levels are elevated in aggressive tumors types when compared with normal tissue or low-grade tumors and is included among lists of genes that predict poor prognosis in patients with various types of cancer. Other studies have shown that elevated levels of soluble OPN in the blood of many cancer patients are correlated with reduced survival. We identified a novel role for OPN in supporting distant tumor outgrowth: soluble OPN secreted from instigating tumors acts in an endocrinal fashion to perturb cells in the bone marrow that are subsequently mobilized into the circulation and recruited into the stroma of tumors at secondary sites, ultimately resulting in the outgrowth of these distant, otherwise-indolent tumors (see model). Our observations that tumor-derived OPN is not sufficient on its own to facilitate outgrowth of distant indolent tumors suggest that other, still-unidentified factors cooperate with OPN to mediate systemic instigation. It is likely that a variety of endocrine and paracrine factors, working in concert, are necessary for various aspects of the systemic instigation cascade. We plan to take various experimental approaches to identify such factors. Thus, we hope to build a molecular framework for understanding the systemic instigation process.

Understanding the role of bone marrow derived cells
Systemic instigation is accompanied by the incorporation of bone marrow derived cells into the stroma of the distant, once-indolent tumors. We found that bone marrow cells are functionally activated prior to their mobilization and that these activated bone marrow cells mimic the systemic effects imparted by instigating tumors. Together with our colleagues in the Hematology Division of Brigham and Women’s Hospital, we are focusing our research efforts on these bone marrow cell type(s) and how they are affected by endocrine factors released into the circulation by instigating tumors.

Uncovering the initiation of stromal desmoplasia
Perhaps the most surprising aspects of the instigation process came from our observations of the histopathology of the resulting tumors. We observed that responding tumors formed with a reactive stroma – a condition that is associated with poor prognosis for cancer patients – only when growing in the presence of a distant instigating tumor. Our results revealed that the formation of desmoplastic stroma is governed to some extent on a systemic level by endocrine factors released by certain instigating tumors.  Currently, very little is known about the processes that mediate desmoplastic tumor growth; therefore we hope to dissect the systemic signals that are responsible for this phenomenon.

Protocols
We have posted several of our lab's most common protocols. Please contact us if you have any questions regarding these procedures.

Reviews
Read the following reviews as background material for our lab's research..