INSTRUCTIONS - PROFESSORS: Please print and review this form. Complete or correct the sections, as applicable, from "Supervisor's Name" to "Ethics, safety, and training". Please sign and date near the bottom ("Supervisor's signature").
INSTRUCTIONS - STUDENTS: You may receive this form by email, or you may download it from www.mcgill.ca/science/research/ours/396 after it has been posted. Either way, print and review this form. Complete or correct the sections, from "Student's Name" to "Student's Level", and sign ("Student signature). Ask your supervisor to sign her/his section near the bottom. Take it to the department corresponding to the course number; this may or may not be your own department. Do not register for a '396' course on Minerva until you receive departmental permission. Have a discussion with your supervisor about time/work expectations, keeping in mind that this is a 3-credit course (roughly, 10 hours per week for 12 weeks). Remember that a '396' course is an elective.
INSTRUCTIONS - DEPARTMENTS: After the unit chair/director/designate approves (or not) this project, please notify student. If approved, please give student permission to register on Minerva, and fax this form (with signatures) to the Office for Undergraduate Research in Science at 514-398-8102. The Office for Undergraduate Research in Science will later post the project online at www.mcgill.ca/science/research/ours/396/listing, indicating whether the project is open for students to apply or taken.
QUESTIONS OR FEEDBACK? Contact Victor Chisholm by email, or phone 514-398-5964
Supervisor's Name: Peter Siegel, Ph.D.
Supervisor's Email: peter [dot] siegel [at] mcgill [dot] ca
Supervisor's Phone: (514) 398-4259
Supervisor's Website: http://www.medicine.mcgill.ca/biochem/siegellab/index.htm
Supervisor's department: Anatomy and Cell Biology
Course number: ANAT396 (Anatomy and Cell Biology)
Term: Winter 2011-2012
Project start date: Monday, January 9, 2012
Project end date: Monday, April 16, 2012
Project title: Defining the mechanisms of claudin-2 mediated breast cancer cell - hepatocyte interactions during the establishment of liver metastases.
Project description: Summary of Research:
Background: Breast cancer is the most commonly diagnosed cancer affecting Canadian women and is the second leading cause of cancer deaths in these patients. The ability of breast cancer cells to spread or "metastasize" to other organs is the most deadly aspect of this disease. The liver is the third most frequent site for breast cancer metastasis, following the bone and lung. Moreover, the 5 year survival rates for breast cancer patients with hepatic metastases remain very low. We have employed 4T1 murine mammary carcinoma cells, isolated via an in vivo selection strategy, which display either a weak or aggressive growth phenotype in the liver. Coincident with the loss of numerous tight-junctional proteins, we observe claudin-2 overexpression specifically in liver-aggressive breast cancer cells. Claudin-2 is a transmembrane protein that is normally a component of tight junctions in polarized epithelium. It contains four transmembrane domains that form two extracellular loops, the first which defines the pore size and ion selectivity of the tight junction and a smaller second loop that facilitates homo- or heterotypic interactions with other claudin family members. We have demonstrated that claudin-2 is both necessary and sufficient for the ability of 4T1 breast cancer cells to colonize and grow in the liver. Finally, immunohistochemical analyses reveal that claudin-2, while weakly expressed in primary human breast cancers, is readily detected in all liver metastasis samples examined to date. Previous data in the literature indicates that breasttumor cells form tight contacts with hepatocytes immediately following colonization of the liver.
Aim: Identify the mechanisms by which Claudin-2 facilitates interactions between breast cancer cells and hepatocytes to enhance survival and growth in the liver.
Method: We hypothesize that claudin-2 may play an important role in breast cancer derived liver metastasis and we are interested in the identification of those processes through which claudin-2 functions to mediate its pro-metastatic effects. Our preliminary data indicates that claudin-2 promotes the ability of breast cancer cells to adhere to primary hepatocytes.
Interestingly, we have identified the second extracellular loop of claudin-2 as an important determinant of the ability of claudin-2 to promote these interactions. Using chimeric molecules composed of a claudin-4 backbone harboring 1) both extracellular loops of claudin-2, 2) the first extracellular loop of claudin-2 or the second extracellular loop of claudin-2. We have established liver-aggressive populations in which we have stably diminished endogenous claudin-2 expression and individually introduced an empty vector control, claudin-4 or chimeric constructs. We have shown that expression of claudin-4 or C4(C2/C4) cannot rescue breast cancer cell adhesion to hepatocytes, whereas C4(C2/C2) and C4(C4/C2) can. This project will focus on assessing the ability of these chimeric claudin molecules to promote breast cancer liver metastasis in vivo.
To accomplish this, the student will perform splenic injections with the 4T1-derived populations described above and quantify the liver metastatic burden at early and late timepoints.
Cancer Significance and learning objectives: The liver represents the third most frequent site for breast cancer metastasis and that breast cancer patients with hepatic metastases display a poor prognosis, with median survival times between 14-16 months and 5 year-survival rates that reach only 5.5-8.5%. This project will reveal how claudin-2 facilitates breast cancer/hepatocyte interactions and define their importance to the ability of breast cancer cells to metastasize to the liver. This project will expose the student to several techniques, including mammalian cell culture and experimental metastasis assays. The student will begin to learn about aspects of breast cancer metastasis ingeneral and the requirements for organ-specific metastasis in particular.
Prerequisite: 1 term completed at McGill + CGPA of 3.0 or higher; or permission of instructor.
Grading scheme (The final report must be worth at least 50% of final grade): 50% from lab performance and 50% from final report
Project status - This project is: Taken; however students may contact the professor to discuss other possible '396' projects this term.
How students can apply: N/A; this project is filled.
Ethics, safety, and training: Supervisors are responsible for the ethics and safety compliance of undergraduate students. This project involves: Animal subjects; Biohazardous substances.
Student's McGill ID:
Student's Email (first [dot] last [at] mail [dot] mcgill [dot] ca):
Student's Level (U0 / U1 / U2 / U3):
Student's signature - I have not applied for another '396' course in this term:
Supervisor's signature - I give my permission for the student identified above to register for this project under my supervision:
Unit chair/director/designate's name:
Unit chair/director/designate's signature - I certify that this project conforms to departmental requirements for 396 courses: