Natalia Molina presents a critical analysis of the period 1924-1965 in U.S. immigration policy and provides an opportunity for readers to examine the racialization of Mexicans in the United States and its impact on immigration legislation and naturalization.

Patients from historically underrepresented racial and ethnic groups are enrolled in cancer clinical trials at disproportionately low rates in the United States 1-3. As these patients often have limited English proficiency4-7, we hypothesized that one barrier to their inclusion is the cost to investigators of translating consent documents. To test this hypothesis, we evaluated more than twelve-thousand consent events at a large Cancer Center and assessed whether patients requiring translated consent documents would sign consent documents less frequently in studies lacking industry sponsorship (for which the principal investigator pays translation costs) than for industry sponsored studies (for which this cost is covered by the sponsor). Here, we show that the proportion of consent events for patients with limited English proficiency in studies not sponsored by industry was approximately half of that seen in industry sponsored studies. We also show that among those signing consent documents, the proportion of consent documents translated into the patient’s primary language in studies without industry sponsorship was approximately half of that seen in industry sponsored studies. Our results suggest that the cost of consent document translation in trials not sponsored by industry is a potentially modifiable barrier to the inclusion of patients with limited English proficiency.

Cancer is a leading cause of death worldwide. During metastasis, cells from a primary tumor escape, invade local tissues and spread to distant organs. Even though this process represents the highest risk for cancer related death, a lot remains unknown about the principles behind its beginning and progression. The main barrier that cancer cells face at each step of the metastatic process is a complex 3D extracellular matrix (ECM), which they need to bind to, pull on and degrade. In this dissertation I use 3D culture systems to mimic a native 3D ECM in vitro, to quantitatively study the role of the ECM structure and physical properties on the development of invasive phenotypes and gene expression programs.

In chapter 1, I identified a switch to a highly persistent and polarized cell motility in a high density environment and discovered that cells undergoing this migration formed multicellular structures. Using RNA sequencing I found an upregulated 70 gene module that together with the motility response has been describes as vasculogenic mimicry (VM). I show evidence that the identified transcriptional program predicts survival in patient data across nine distinct tumor types, suggesting it may represent a conserved metastatic response.

In chapter 2, I investigate the biophysical mechanisms of cell-ECM interactions. I find that matrices with low degradability limit cell adhesion. Cells in these matrices display hallmarks of anchorage independent growth, including oxidative stress. They show decreased expression of several mTOR target genes and downregulation of TCA cycle and pyruvate metabolism pathways. Lastly, I show that as part of the response to low adhesion state, cells upregulate key NOTCH signaling molecules.

In chapter 3, I propose the use of in vivo models to deconstruct the role of collagen density in promoting cancer cell metastasis. I present preliminary data and future directions for these in vivo models.

The data presented in this dissertation provides a multiscale view of the role of the collagen microenvironment in the development of cancer cell invasive motility and metastatic phenotypes. The discoveries presented hereby highlight the value of using 3D culture assays in combination with quantitative analysis to uncover biological phenomenon with high translational potential.