Session 7

Hematogenous metastasis is a complicated and inefficient multistep process by which tumor cells spread via blood circulation to form secondary tumors in distant organs throughout the body. Only a very small fraction of the circulating tumor cells (CTCs) shed into the bloodstream is able to initiate a metastasis. Our research is focusing on understanding the molecular properties of these metastatic "seeds" and their interactions with the local organ microenvironment or "soil". To identify the metastasis-initiating CTCs, we ex vivo expanded CTCs derived from breast cancer patients and inoculated them into the bloodstreams of immunocompromised mice and identified metastases in the common sites of breast cancer: lung, bone, brain. Importantly, the metastatic patterns in mice reflected those in the corresponding patients. Particularly, one CTC line showed a high capacity for brain metastasis in mice, which preceded the clinical detection of brain metastasis in the corresponding patient by one year. Serial in vivo inoculation showed increased organotropisms, further proving the intrinsic tendency of these cells to initiate metastasis in specific organs. Via genetic, epigenetic and transcriptional analyses, we revealed genes associated with organotropic features and identified drivers for brain metastasis. Through functional validation, we found that the semaphorin family cell surface receptor SEMA4D and oncogene MYC work together to promote brain metastasis, by promoting blood-brain barrier (BBB) transmigration and colonization, two orthogonal steps of brain metastasis. To further investigate the metastatic capacity of CTCs, our recent research discovered a "hypoxia-exposure memory" that provides a long-lasting effect from the solid tumors on CTCs to promote metastasis. Ongoing research is focusing on elucidating the underlying mechanisms of this novel finding in CTCs, with the goal to uncover vulnerabilities for novel therapies.

Beyond contributing a haploid genome to the next generation, germ cells also transmit so-called "epigenetic" information with the potential to influence offspring phenotype. Over the past two decades, we and others have shown that ancestral environmental conditions can impact metabolic and other phenotypes in the next generation, a phenomenon clearly related to the once-discredited idea of "inheritance of acquired characters." 
Our lab has developed several models for transmission of epigenetic information through the male germline in mammals, exploring how paternal diets or drug exposures program metabolism and behavior in offspring. I will discuss our efforts to understand these systems mechanistically, focusing primarily on surprising features of the sperm RNA payload, including: 1) a central role for germline accessory tissues in shaping the sperm epigenome; 2) control of preimplantation development and gene regulation by sperm-delivered RNAs, and; 3) functional roles (in the embryo and elsewhere) for an understudied class of regulatory small RNAs derived from mature tRNAs, known as tRNA fragments.

Click Here for Recorded Presentation

Despite decreased susceptibility, darker skin individuals who develop melanoma have worse survival. This disparity in melanoma mortality is the largest for any cancer, and partly driven by a lack of educational materials targeted to darker skin populations in whom acral lentiginous melanoma (ALM) is the most common subtype. To address this communication disparity, the current study reports a multi-phase design process that leverages crowdsourcing and message testing to develop ALM-focused educational materials for darker skin populations. Crowdsourced design was utilized to develop a pool of designs (phase 1), the pool was narrowed and thematically analyzed (phase 2), and select designs were evaluated via a message experiment (N = 1,877). For darker skin populations, designs that depicted people enhanced knowledge of ALM through message memorability. The current study engages melanoma disparities by providing ALM educational materials for darker skin populations vetted via a multi-phase process. 

Click Here for Recorded Presentation